Highly Stable 72-Nuclearity Nanocages for Efficient Synthesis of Aryl Nitriles via Ni/Cu Synergistic Catalysis.

Seeking noble-metal-free catalysts for efficient synthesis of aryl nitriles under mild conditions poses a significant challenge due to the use of hypertoxic cyanides or high-pressure/temperature NH3/O2 in conventional synthesis processes. Herein, we developed a novel framework 1 assembled by [Ni72] nanocages with excellent solvents/pH stability. To investigate the structure-activity relationship of catalytic performance, several isostructural MOFs with different molar ratios of Ni/Cu by doping Cu2+ into framework 1 (Ni0.59Cu0.41 (2), Ni0.81Cu0.19 (3), Ni0.88Cu0.12 (4), and Ni0.92Cu0.08 (5)) were prepared. Catalytic studies revealed that catalyst 3 exhibited remarkable performance in the synthesis of aryl nitriles, utilizing a formamide alternative to hypertoxic NaCN/KCN. Notably, catalyst 3 achieved an excellent TOF value of 9.8 h-1. Furthermore, catalyst 3 demonstrated its applicability in a gram-scale experiment and maintained its catalytic performance even after six recycling cycles, owing to its high stability resulting from significant electrostatic and orbital interactions between the Ni center and ligands as well as a large SOMO-LUMO energy gap supported by DFT calculations. Control experiments and DFT calculations further revealed that the excellent catalytic performance of catalyst 3 originated from the synergistic effect of Ni/Cu. Importantly, this work not only provides a highly feasible method to construct highly stable MOFs containing multinuclear nanocages with exceptional catalytic performance but also represents the first example of a heterogeneous catalyst for the synthesis of aryl nitriles using formamide as the cyanide source.

R-loop and diseases: the cell cycle matters.

The cell cycle is a crucial biological process that is involved in cell growth, development, and reproduction. It can be divided into G1, S, G2, and M phases, and each period is closely regulated to ensure the production of two similar daughter cells with the same genetic material. However, many obstacles influence the cell cycle, including the R-loop that is formed throughout this process. R-loop is a triple-stranded structure, composed of an RNA: DNA hybrid and a single DNA strand, which is ubiquitous in organisms from bacteria to mammals. The existence of the R-loop has important significance for the regulation of various physiological processes. However, aberrant accumulation of R-loop due to its limited resolving ability will be detrimental for cells. For example, DNA damage and genomic instability, caused by the R-loop, can activate checkpoints in the cell cycle, which in turn induce cell cycle arrest and cell death. At present, a growing number of factors have been proven to prevent or eliminate the accumulation of R-loop thereby avoiding DNA damage and mutations. Therefore, we need to gain detailed insight into the R-loop resolution factors at different stages of the cell cycle. In this review, we review the current knowledge of factors that play a role in resolving the R-loop at different stages of the cell cycle, as well as how mutations of these factors lead to the onset and progression of diseases.

GetPrimers: A generalized PCR-based genetic targeting primer designer enabling easy and standardized targeted gene modification across multiple systems.

Genetic targeting (e.g., gene knockout and tagging) based on polymerase chain reaction (PCR) is a simple yet powerful approach for studying gene functions. Although originally developed in classic budding and fission yeast models, the same principle applies to other eukaryotic systems with efficient homologous recombination. One-step PCR-based genetic targeting is conventionally used but the sizes of the homologous arms that it generates for recombination-mediated genetic targeting are usually limited. Alternatively, gene targeting can also be performed via fusion PCR, which can create homologous arms that are orders of magnitude larger, therefore substantially increasing the efficiency of recombination-mediated genetic targeting. Here, we present GetPrimers (https://www.evomicslab.org/app/getprimers/), a generalized computational framework and web tool to assist automatic targeting and verification primer design for both one-step PCR-based and fusion PCR-based genetic targeting experiments. Moreover, GetPrimers by design runs for any given genetic background of any species with full genome scalability. Therefore, GetPrimers is capable of empowering high-throughput functional genomic assays at multipopulation and multispecies levels. Comprehensive experimental validations have been performed for targeting and verification primers designed by GetPrimers across multiple organism systems and experimental setups. We anticipate GetPrimers to become a highly useful and popular tool to facilitate easy and standardized gene modification across multiple systems.

The role of ADAR1 through and beyond its editing activity in cancer.

Adenosine-to-inosine (A-to-I) editing of RNA, catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes, is a prevalent RNA modification in mammals. It has been shown that A-to-I editing plays a critical role in multiple diseases, such as cardiovascular disease, neurological disorder, and particularly cancer. ADARs are the family of enzymes, including ADAR1, ADAR2, and ADAR3, that catalyze the occurrence of A-to-I editing. Notably, A-to-I editing is mainly catalyzed by ADAR1. Given the significance of A-to-I editing in disease development, it is important to unravel the complex roles of ADAR1 in cancer for the development of novel therapeutic interventions.In this review, we briefly describe the progress of research on A-to-I editing and ADARs in cancer, mainly focusing on the role of ADAR1 in cancer from both editing-dependent and independent perspectives. In addition, we also summarized the factors affecting the expression and editing activity of ADAR1 in cancer.

Discovery of Selective and Potent ATR Degrader for Exploration its Kinase-Independent Functions in Acute Myeloid Leukemia Cells.

ATR has emerged as a promising target for anti-cancer drug development. Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase-independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis-targeting chimera (PROTAC) molecule as a probe. The ATR degrader, 8 i, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor 1. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53-mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti-proliferative effects of ATR degrader 8 i were assessed using xenograft models. The degrader significantly inhibited the growth of AML cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti-AML activity is regulated by the kinase-independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML.

Effect of 3-Dimensional Imaging Device on Polyp and Adenoma Detection During Colonoscopy: A Randomized Controlled Trial.

INTRODUCTION: To evaluate the effect of 3-dimensional (3D) imaging device on polyp and adenoma detection during colonoscopy. METHODS: In a single-blind, randomized controlled trial, participants aged 18-70 years who underwent diagnostic or screening colonoscopy were consecutively enrolled between August 2019 and May 2022. Each participant was randomized in a 1:1 ratio to undergo either 2-dimensional (2D-3D) colonoscopy or 3D-2D colonoscopy through computer-generated random numbers. Primary outcome included polyp detection rate (PDR) and adenoma detection rate (ADR), defined as the proportion of individuals with at least 1 polyp or adenoma detected during colonoscopy. The primary analysis was intention-to-treat. RESULTS: Of 1,196 participants recruited, 571 in 2D-3D group and 583 in 3D-2D group were finally included after excluding those who met the exclusion criteria. The PDR between 2D and 3D groups was separately 39.6% and 40.5% during phase 1 (odds ratio [OR] = 0.96, 95% confidence interval [CI]: 0.76-1.22, P = 0.801), whereas PDR was significantly higher in 3D group (27.7%) than that of 2D group (19.9%) during phase 2, with a 1.54-fold increase (1.17-2.02, P = 0.002). Similarly, the ADR during phase 1 between 2D (24.7%) and 3D (23.8%) groups was not significant (OR = 1.05, 0.80-1.37, P = 0.788), while ADR was significantly higher in 3D group (13.8%) than that of 2D group (9.9%) during phase 2, with a 1.45-fold increase (1.01-2.08, P = 0.041). Further subgroup analysis confirmed significantly higher PDR and ADR of 3D group during phase 2, particularly in midlevel and junior endoscopists. DISCUSSION: The 3D imaging device could improve overall PDR and ADR during colonoscopy, particularly in midlevel and junior endoscopists. Trial number: ChiCTR1900025000.

Effects of stacking breeding on the methylome and transcriptome profile of transgenic rice with glyphosate tolerance.

MAIN CONCLUSION: Transcriptomics and methylomics were used to identify the potential effects resulting from GM rice breeding stacks, which provided scientific data for the safety assessment strategy of stacked GM crops in China. Gene interaction is one of the main concerns for stacked genetically modified crop safety. With the development of technology, the combination of omics and bioinformatics has become a useful tool to evaluate the unintended effects of genetically modified crops. In this study, transcriptomics and methylomics were used as molecular profiling techniques to identify the potential effects of stack through breeding. Stacked transgenic rice En-12 × Ec-26 was used as material, which was obtained through hybridization using parents En-12 and Ec-26, in which the foreign protein can form functional EPSPS protein by intein-mediated trans-splitting. Differentially methylated region (DMR) analysis showed that the effect of stacking breeding on methylation was less than that of genetic transformation at the methylome level. Differentially expressed gene (DEG) analysis showed that the DEGs between En-12 × Ec-26 and its parents were far fewer than those between transgenic rice and Zhonghua 11 (ZH11), and no unintended new genes were found in En-12 × Ec-26. Statistical analysis of gene expression and methylation involved in shikimic acid metabolism showed that there was no difference in gene expression, although there were 16 and 10 DMR genes between En-12 × Ec-26 and its parents (En and Ec) in methylation, respectively. The results indicated that the effect of stacking breeding on gene expression and DNA methylation was less than the effect of genetic transformation. This study provides scientific data supporting safety assessments of stacked GM crops in China.

Design and discovery of new selective and potent VEGF receptor 2 tyrosine kinase inhibitors.

A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared by 3D modeling as potential inhibitors of VEGFR-2. Evaluation of VEGFR inhibitory activities suggested that compound I10 was a more potent (IC50 = 0.11 nM) VEGFR-2 inhibitor than most of the listed drugs. Kinase panel assays demonstrated that compound I10 was the selective VEGFR-2 inhibitor. The prediction of 3D modeling unveiled a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable anti-angiogenesis and anti-proliferation in HUVEC at low nanomolar concentrations. PK studies indicated that the lead compound possessed adequate oral bioavailability in various species. In vivo subcutaneous tumor model demonstrated that oral administration of I10 demonstrated potent efficacy in inhibiting tumor growth and angiogenesis. All these results suggested compound I10 is a potential drug candidate for cancer treatment.

High Protein Whole Food Snack and Albumin Outcomes in Patients With Dialysis-Dependent Chronic Kidney Disease.

OBJECTIVE: Protein-energy wasting is common among patients on hemodialysis (HD). This study sought to define effects that a novel, post-HD, high-calorie, high-protein whole food snack had on patients' serum albumin (serum alb), serum phosphorus and equilibrated normalized protein catabolic rate (enPCR). METHODS: A 12-month (6 months intervention, 6 months pre/post data collection), single-center, unblinded study was conducted. Participants (n = 67) consumed, ad libitum, a whole food snack post-HD for 6 treatments each month. Upon analysis, regression models identified relationships between serum alb and whole food snack consumption across follow up. Predefined effect size anticipated was + 0.2 g/dL. Patients were stratified by high (≥4 g/dL) or low (<4 g/dL) mean serum alb during a 3-month baseline period. Paired t-tests compared mean per patient difference in serum alb, enPCR and serum phosphorus from baseline to each month of follow up, stratified by high (≥640 g) or low (<640 g) consumption of the whole food snack (a priori caloric estimation). RESULTS: Linear regression models showed positive associations between higher serum alb and enPCR with higher whole food snack consumption across follow up (all P < .05). Assessments from baseline to each follow-up month show some increases in serum alb, yet t test comparisons were not significant. No significant changes were seen in serum phosphorus levels during follow-up. CONCLUSION: Albeit the catabolic effects of HD are well-known, effective nutritional interventions are scarce. Results showed that providing a whole food snack post-HD to individuals with serum alb <4.0 g/dL may be beneficial but further studies are recommended.

Transcutaneous electrical cranial-auricular acupoint stimulation versus escitalopram for mild-to-moderate depression: An assessor-blinded, randomized, non-inferiority trial.

AIM: Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is a novel non-invasive therapy that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. An assessor-blinded, randomized, non-inferiority trial was designed to compare the efficacy of TECAS and escitalopram in mild-to-moderate major depressive disorder. METHODS: 468 participants received two TECAS sessions per day at home (n = 233) or approximately 10-13 mg/day escitalopram (n = 235) for 8 weeks plus 4-week follow-up. The primary outcome was clinical response, defined as a baseline-to-endpoint ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Secondary outcomes included remission rate, changes in the severity of depression, anxiety, sleep and life quality. RESULTS: The response rate was 66.4% on TECAS and 63.2% on escitalopram with a 3.2% difference (95% confidence interval [CI], -5.9% to 12.9%) in intention-to-treat analysis, and 68.5% versus 66.2% with a 2.3% difference (95% CI, -6.9% to 11.4%) in per-protocol analysis. The lower limit of 95% CI of the differences fell within the prespecified non-inferiority margin of -10% (P ≤ 0.004 for non-inferiority). Most secondary outcomes did not differ between the two groups. TECAS-treated participants who experienced psychological trauma displayed a markedly greater response than those without traumatic experience (81.3% vs 62.1%, P = 0.013). TECAS caused much fewer adverse events than escitalopram. CONCLUSIONS: TECAS was comparable to escitalopram in improving depression and related symptoms, with high acceptability, better safety profile, and particular efficacy in reducing trauma-associated depression. It could serve an effective portable therapy for mild-to-moderate depression.

Detection of Various Traditional Chinese Medicinal Metabolites as Angiotensin-Converting Enzyme Inhibitors: Molecular Docking, Activity Testing, and Surface Plasmon Resonance Approaches.

Angiotensin-converting enzyme 1 (ACE1) is a peptide involved in fluid and blood pressure management. It regulates blood pressure by converting angiotensin I to angiotensin II, which has vasoconstrictive effects. Previous studies have shown that certain compounds of natural origin can inhibit the activity of angiotensin-converting enzymes and exert blood pressure-regulating effects. Surface Plasmon Resonance (SPR) biosensor technology is the industry standard method for observing biomolecule interactions. In our study, we used molecular simulation methods to investigate the docking energies of various herbal metabolites with ACE1 proteins, tested the real-time binding affinities between various herbal metabolites and sACE1 by SPR, and analyzed the relationship between real-time binding affinity and docking energy. In addition, to further explore the connection between inhibitor activity and real-time binding affinity, several herbal metabolites' in vitro inhibitory activities were tested using an ACE1 activity test kit. The molecular docking simulation technique's results and the real-time affinity tested by the SPR technique were found to be negatively correlated, and the virtual docking technique still has some drawbacks as a tool for forecasting proteins' affinities to the metabolites of Chinese herbal metabolites. There may be a positive correlation between the enzyme inhibitory activity and the real-time affinity detected by the SPR technique, and the results from the SPR technique may provide convincing evidence to prove the interaction between herbal metabolites and ACE1 target proteins.

Site-directed RNA editing by harnessing ADARs: advances and challenges.

Adenosine deaminase acting on RNA (ADAR) enzyme-mediated A-to-I RNA editing is widely distributed in the transcriptome. It plays an important role in autoimmune surveillance, tumorigenesis, and development. Recently, several site-directed RNA editing (SDRE) systems have been developed to target disease causative point mutations by flexibly exploiting the catalytic adenosine deamination properties of ADARs. This is based on the fact that A-to-I RNA editing is essentially an adenosine-guanine transition. In contrast to genome editing, RNA editing is tunable and transient, and there are still some shortcomings that need to be addressed. Here, we outline several SDRE systems that rely on the catalytic deamination activity of endogenous or exogenous ADARs, attempting to illustrate their strategies and discuss numerous shortcomings that need to be overcome in the future.

PI3K/AKT1 Signaling Pathway Mediates Sinomenine-Induced Hepatocellular Carcinoma Cells Apoptosis: An in Vitro and in Vivo Study.

Hepatocellular carcinoma (HCC) is one of the most frequent cancers. Sinomenine (SIN) is a compound derived from Sinomenium acutum. Our previous investigations have found that SIN inhibited protein kinase B (AKT) signaling to induce autophagic death of tumor cells. However, whether inhibition of this pathway by SIN could impact the proliferation of HCC cells is unknown. Thus, we applied SIN to SK-Hep-1 cells and used cell counting kit 8 (CCK8), lactate dehydrogenase (LDH), colony formation and 5-ethynyl-20-deoxyuridine (EdU) incorporation experiments to detect cell viability. Then, staining with annexin V/propidium iodide (PI) coupled with terminal deoxynucleotidyl transferase-mediated biotinylated uridine 5'-triphosphate (UTP) nick end labeling (TUNEL) staining were utilized to monitor apoptosis. Changes in cell mitochondrial membrane capacity were explored via 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, whilst Western blot or immunohistochemistry was applied to evaluate the expression levels of key proteins, consisting of Cleaved Caspase 3, AKT1, B-cell leukemia/lymphoma 2 (BCL-2), phosphatidylinositol 3-kinase (PI3K) p85α, and Cleaved Caspase 9 etc. The Balb/c nude mice were utilized to establish HCC xenograft tumor model, administered by SIN. After treatments, the tumor volume along with weight were measured. The results illustrated that SIN suppressed SK-Hep-1 HCC cells' proliferation, enhanced the collapse of potential of the mitochondrial membrane, triggered cell apoptosis, down-regulated PI3K p85α, AKT1, BCL-2, Pro-Caspase 9, Pro-Caspase 3 expressions, and up-regulated Cleaved Caspase 9 and Cleaved Caspase 3 expressions in vitro and in vivo. Meanwhile, SIN reduced the tumor volume along with weight of mice. In addition, insulin-like growth factor-1 (IGF-1), a powerful activator of the PI3K/AKT pathway, could reverse the high apoptosis of SK-Hep-1 HCC cells induced by SIN. Overall, inhibition of PI3K/AKT1 signaling cascade by SIN induced HCC cells apoptosis.

sh-HNF1A-AS1 reduces the epithelial-mesenchymal transition and stemness of esophageal cancer cells.

HNF1A-AS1 is a cancer-related lncRNA. Elevated expression of HNF1A-AS1 has been observed in various malignancies including esophageal squamous cell carcinoma (ESCC). However, the role of HNF1A-AS1 in ESCC has not been fully understood. This study aimed to investigate the potential role of HNF1A-AS1 in ESCC. Expression of HNF1A-AS1, miRNA (miR)-298, and transcription factor 4 (TCF4) was detected using qRT-PCR. The interactions between HNF1A-AS1 and miR-298 or miR-298 and TCF4 were evaluated. Short hairpin RNAs (shRNAs) were used to knock down HNF1A-AS1 (sh-HNF1A-AS1). The EMT and stemness of ESCC cells were detected. HNF1A-AS1 was overexpressed in ESCC tumor tissues and cells. miR-298 was validated as a direct target of HNF1A-AS1. sh-HNF1A-AS1 significantly inhibited EMT and stemness of ESCC cells. The high expression of miR-298 significantly inhibited the expression of TCF4, and further inhibited the expression of N-cadherin and stemness-related genes. Animal experiments showed that sh-HNF1A-AS1 significantly inhibited tumor growth and increased the level of miR-298 in tissues. In conclusion, knockdown of HNF1A-AS1 could inhibit EMT and stemness by regulating the miR-298/TCF4 axis.

Cephalic arch restenosis rates in hemodialysis patients with brachiocephalic fistulae: a retrospective multicenter analysis of 3301 patients.

BACKGROUND: We evaluated restenosis rates at the cephalic arch after percutaneous angioplasty and stenting procedures in patients with brachial artery to cephalic vein arteriovenous fistula (BCAVF) hemodialysis access. METHODS: We used data from adult hemodialysis patients treated at a national network of 44 outpatient interventional facilities during Oct 2011-2015. We included data from patients with BCAVF who received an exclusive angioplasty, or stent with angioplasty, for treatment of cephalic arch stenosis and had ≥1 subsequent evaluation of the cephalic arch. Median percent restenosis per month at cephalic arch and days between encounters was calculated from the 1st index to 2nd procedure, and for up to 4 subsequent encounters. Analyses were stratified by intervention and device types. RESULTS: We identified a cohort of 3301 patients (mean age 62.2 ± 13.9 years, 58.5% male, 33.2% white race) with a BCAVF who had an angioplasty, or stent, at the cephalic arch for an index and ≥ 1 follow-up procedure. Between the 1st index to 2nd procedure, patients who received an angioplasty (n = 2663) or stent (n = 933) showed a median decrease of 18.9 and 16.5% in luminal diameter per month and a median time of 93 and 91 days between encounters, respectively. Restenosis and day rates were similar for standard versus high-pressure angioplasties. Bare metal stents showed 10.1 percentage point higher restenosis rate compared to stent grafts. Restenosis rates and time to restenosis were relatively consistent across subsequent encounters. CONCLUSIONS: Findings suggest hemodialysis patients with a BCAVF who require an angioplasty or stent to treat a stenosis at the cephalic arch will have stenosis reformed at a rate of 18.9 and 16.5% per month after the first intervention, respectively. Findings suggest patients are at risk of having significant lesions at the cephalic arch within 3 months after the previous intervention.

Predictors of shorter- and longer-term mortality after COVID-19 presentation among dialysis patients: parallel use of machine learning models in Latin and North American countries.

BACKGROUND: We developed machine learning models to understand the predictors of shorter-, intermediate-, and longer-term mortality among hemodialysis (HD) patients affected by COVID-19 in four countries in the Americas. METHODS: We used data from adult HD patients treated at regional institutions of a global provider in Latin America (LatAm) and North America who contracted COVID-19 in 2020 before SARS-CoV-2 vaccines were available. Using 93 commonly captured variables, we developed machine learning models that predicted the likelihood of death overall, as well as during 0-14, 15-30, > 30 days after COVID-19 presentation and identified the importance of predictors. XGBoost models were built in parallel using the same programming with a 60%:20%:20% random split for training, validation, & testing data for the datasets from LatAm (Argentina, Columbia, Ecuador) and North America (United States) countries. RESULTS: Among HD patients with COVID-19, 28.8% (1,001/3,473) died in LatAm and 20.5% (4,426/21,624) died in North America. Mortality occurred earlier in LatAm versus North America; 15.0% and 7.3% of patients died within 0-14 days, 7.9% and 4.6% of patients died within 15-30 days, and 5.9% and 8.6% of patients died > 30 days after COVID-19 presentation, respectively. Area under curve ranged from 0.73 to 0.83 across prediction models in both regions. Top predictors of death after COVID-19 consistently included older age, longer vintage, markers of poor nutrition and more inflammation in both regions at all timepoints. Unique patient attributes (higher BMI, male sex) were top predictors of mortality during 0-14 and 15-30 days after COVID-19, yet not mortality > 30 days after presentation. CONCLUSIONS: Findings showed distinct profiles of mortality in COVID-19 in LatAm and North America throughout 2020. Mortality rate was higher within 0-14 and 15-30 days after COVID-19 in LatAm, while mortality rate was higher in North America > 30 days after presentation. Nonetheless, a remarkable proportion of HD patients died > 30 days after COVID-19 presentation in both regions. We were able to develop a series of suitable prognostic prediction models and establish the top predictors of death in COVID-19 during shorter-, intermediate-, and longer-term follow up periods.

Gene- and pathway-level analyses of iCOGS variants highlight novel signaling pathways underlying familial breast cancer susceptibility.

Single-nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome-wide association studies involving mostly unselected population-based case-control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC-prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP-level analysis using index cases and controls, we performed pedigree-based association tests to capture transmission information in the sibships. We also performed gene- and pathway-level analyses to maximize the power to detect associations with lower-frequency SNPs or those with modest effect sizes. While SNP-level analyses identified 18 loci, gene-level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the "index case-control" analysis, we built pathway-derived polygenic risk scores (PRS) and assessed their performance in the population-based CECILE study and in a data set composed of GENESIS-affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP-level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.

A new hybrid record linkage process to make epidemiological databases interoperable: application to the GEMO and GENEPSO studies involving BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Linking independent sources of data describing the same individuals enable innovative epidemiological and health studies but require a robust record linkage approach. We describe a hybrid record linkage process to link databases from two independent ongoing French national studies, GEMO (Genetic Modifiers of BRCA1 and BRCA2), which focuses on the identification of genetic factors modifying cancer risk of BRCA1 and BRCA2 mutation carriers, and GENEPSO (prospective cohort of BRCAx mutation carriers), which focuses on environmental and lifestyle risk factors. METHODS: To identify as many as possible of the individuals participating in the two studies but not registered by a shared identifier, we combined probabilistic record linkage (PRL) and supervised machine learning (ML). This approach (named "PRL + ML") combined together the candidate matches identified by both approaches. We built the ML model using the gold standard on a first version of the two databases as a training dataset. This gold standard was obtained from PRL-derived matches verified by an exhaustive manual review. Results The Random Forest (RF) algorithm showed a highest recall (0.985) among six widely used ML algorithms: RF, Bagged trees, AdaBoost, Support Vector Machine, Neural Network. Therefore, RF was selected to build the ML model since our goal was to identify the maximum number of true matches. Our combined linkage PRL + ML showed a higher recall (range 0.988-0.992) than either PRL (range 0.916-0.991) or ML (0.981) alone. It identified 1995 individuals participating in both GEMO (6375 participants) and GENEPSO (4925 participants). CONCLUSIONS: Our hybrid linkage process represents an efficient tool for linking GEMO and GENEPSO. It may be generalizable to other epidemiological studies involving other databases and registries.

[Mechanism of Chuanxiong Rhizoma intervention on central sensitization of Panx1-Src-NMDAR-2B signaling pathway in neuropathic pain model rats].

Excitatory toxicity(ET) is an important factor of neuropathic pain(NPP) induced by central sensitization(CS), and the association of pannexin-1(Panx1)-Src-N-methyl-D-aspartate receptor subunit 2 B(NMDAR-2 B) is an important new pathway for ET to initiate CS. The present study confirmed whether the central analgesic effect of Chuanxiong Rhizoma extract(CRE) was achieved through the synchronous regulation of the brain and spinal pathways of Panx1-Src-NMDAR-2 B. In this study, dynamic and simulta-neo-us microdialysis of the brain and spinal cord in vivo combined with behavioristics, high performance liquid chromatography(HPLC)-fluorescence detection, microdialysis analysis(ISCUS~(flex)), ultrasensitive multifactorial electrochemiluminescence immunoassay, ELISA, and Western blot was employed to investigate the protein expression of NMDAR-2 B, Src, and Panx1, extracellular excitatory amino acids, cytokines, energy metabolites, and substance P in spinal dorsal horn(SDH) and anterior cingulate cortex(ACC) after CRE intervention with the rat model of spared sciatic nerve injury(SNI) as the experimental tool. Compared with the sham group, the SNI group exhibited diminished mechanical withdrawal threshold(MWT)(P<0.01), increased cold spray scores(P<0.01), glutamate(Glu), D-serine(D-Ser), and glycine(Gly) in extracellular fluids of ACC, and Glu, D-Ser, interleukin-1ß(IL-1ß), and lactic acid(Lac) in extracellular fluids of SDH(P<0.05), dwindled tumor necrosis factor(TNF-α)(P<0.05), and elevated protein levels of NMDAR-2 B, Src, and Panx1 in ACC(P<0.05). Compared with the SNI model rats, high-and medium-dose CRE(CRE-H/M) could potentiate the analgesic activity as revealed by the MWT test(P<0.05) and CRE-M enabled the decrease in cold spray scores(P<0.05). CRE-H/M could inhibit the levels of Glu, D-Ser and Gly in the extracellular fluids of ACC(P<0.05), and the levels of Glu in the extracellular fluids of SDH(P<0.05) in SNI rats. CRE-M significantly increased the levels of glucose(Gluc), Lac, interferon-gamma(IFN-γ), keratinocyte chemoattractant/human growth-regulated oncogenes(KC/GRO), and IL-4 in extracellular fluids of SDH in SNI rats(P<0.05). CRE-H/M/L could also inhibit the levels of NMDAR-2 B, Src and Panx1 in ACC and SDH in SNI rats(P<0.05). The central analgesic effect of CRE is presumedly related to the inhibited release of excitatory amino acid transmitters(Glu, D-Ser and Gly) in ACC and SDH of SNI rats, decreased protein expression of NMDAR-2 B, Src and Panx1 in the two regions, and the regulation of the Panx1-Src-NMDAR-2 B pathway in the spinal cord and brain. The above findings partially clarified the scientific basis of clinical analgesic effect of Chuanxiong Rhizoma.

Green Conversion of CO2 and Propargylamines Triggered by Triply Synergistic Catalytic Effects in Metal-Organic Frameworks.

Cyclization of propargylamines with CO2 to obtain 2-oxazolidone heterocyclic compounds is an essential reaction in industry but it is usually catalyzed by noble-metal catalysts with organic bases as co-catalysts under harsh conditions. We have synthesized a unique CuI /CuII mixed valence copper-based framework {[(CuI 6 I5 )Cu3 II L6 (DMA)3 ](NO3 )⋅9DMA}n (1) with good solvent and thermal stability, as well as a high density of uncoordinated amino groups evenly distributed in the large nanoscopic channels. Catalytic experiments show that 1 can effectively catalyze the reaction of propargylamines with CO2 , and the yield can reach 99 %. The turnover frequency (TOF) reaches a record value of 230 h-1 , which is much higher than that of reported noble-metal catalysts. Importantly, this is the first report of heterogeneously catalyzed green conversion of propargylamines with CO2 without solvents and co-catalysts under low temperature and atmospheric pressure. A mechanistic study reveals that a triply synergistic catalytic effect between CuI /CuII and uncoordinated amino groups promotes highly efficient and green conversion of CO2 . Furthermore, 1 directly catalyzes this reaction with high efficiency when using simulated flue gas as a CO2 source.